Tissue damage may result from physical injury, infection, exposure to toxins, auto-immune processes and other causes. The physiological process of normal wound repair after tissue injury involves inflammation, the recruitment, activation and proliferation of fibroblasts and the secretion of extracellular matrix. This response ordinarily culminates in healing and termination of the proliferative and secretory processes. However, in clinically diverse conditions, the fibroproliferative response becomes itself detrimental and produces an abnormal accumulation of fibrocellular scar tissue that further compromises the normal architecture and function of the affected tissue and, in time, becomes the main cause for morbidity and mortality in these conditions.
As shown schematically in FIG. 1, injuries to normal tissues result in production of reactive oxidative species (ROS) and the release of cytokines, including TNF-α, PDGF, ET-1, bFGF, VEGF, TGF-β1 and chemokines CCL2 and CCL7. Mononuclear cells (monocytes/macrophages and neutrophils), T-lymphocytes and fibroblasts are recruited to the injury site. In response to released cytokines, these cells become activated and are a source for pro-fibrotic cytokines, namely TGF-β1 and CTGF. “Activated” fibroblasts trans-differentiate into myofibroblasts which are collagen type I producing cells. The final result is aberrant tissue remodeling, fibrosis and permanent scarring.
Pathological fibrosis can occur in almost any organ or tissue in the body. Examples include, but are not limited to:                1) All forms of pulmonary fibrosis from coal miners' Black Lung Disease to the treatment-induced varieties occurring in cancer patients and premature babies. Typically fibrocellular scar tissue severely reduces lung diffusion capacity, vital capacity and progresses relentlessly to respiratory failure and death.        2) All forms of liver fibrosis and cirrhosis.        3) All forms of vascular fibrosis such as atherosclerosis and diabetic complications.        4) All forms of renal fibrosis.        5) All forms of interventional therapy triggered fibrosis such as restenosis of blood vessels after balloon angioplasties and atherectomies.        
These fibroses are the cause of much suffering, disability and death in millions of patients across the world.
In recent years, due to growing understanding of biochemical and molecular events underlying the progression of fibrosis in whatever organ is affected, reasonable scientific strategies have been generated and, as a result, several experimental drugs for treatment or prophylaxis of fibrosis are in clinical trials and there is considerable optimism that additional new therapies will emerge in the years ahead.
Typically, treatment of fibroproliferative disorders comprises removal of the underlying cause (e.g., toxin or infectious agent), suppression of inflammation (using, e.g., corticosteroids and immunosuppressive agents such cyclophosphamide and azathioprine), inhibition of fibroblast-like cell proliferation (using colchicines, penicillamine), down-regulation of cytokine machinery (using anti-TGF-beta antibodies, endothelin receptor inhibitors, interferons, pirfenidone and others), promotion of matrix degradation (using inhibitors of matrix metalloproteinases), or promotion of fibroblast apoptosis. Despite recent progress, many of these strategies are still in the experimental stage, and existing therapies are largely aimed at suppressing inflammation rather than addressing the underlying biochemical processes. Thus, there remains a need for more effective methods for treating fibroproliferative disorders.
Studies have demonstrated that pentoxifylline (PTX) is capable of positively effecting fibroproliferative disorders in a multi-potent manner. First, as a pan-phosphodiesterase inhibitor, pentoxifylline improves microcirculation and tissue oxygenation of the fibrotic tissue [1-3]; second, pentoxifylline alters the biochemical and physical properties of platelets thus decreasing platelet aggregation in fibrotic tissues [4]; third, pentoxifylline exerts significant anti-cytokine and anti-inflammatory activity, as it is principally capable of inhibiting the pro-inflammatory actions of interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) on neutrophil function and cytokine production by monocytic cells [5]. Finally, pentoxifylline has shown direct inhibition of proliferation and collagen synthesis of human fibroblasts derived from normal and keloid skin and from hypertrophic scars [6]. Other phosphodiesterase inhibitors have some or all of the effects of pentoxifylline [19, 20].
Use of pentoxifylline as the sole agent in the treatment of liver and other fibrosis is claimed in U.S. Pat. No. 5,985,592 to Peterson entitled Uses for Pentoxifylline or Functional Derivatives/Metabolites Thereof. It is well known that fibroproliferative disorders are characterized by an accumulation of immunomodulatory cells (macrophages and neutrophils), parenchymal injury, and fibrosis [7]. Those cells in the affected tissue release exaggerated amounts of highly reactive oxygen radicals (oxidants), which mediate the parenchymal cell damage that typifies fibroproliferative disorders [21-24]. This oxidant burden is even more consequential due to a deficiency of glutathione, the major component of the antioxidant defense systems that normally protect against oxidant induced injury [8, 9].
In addition, low glutathione levels seem to play a major role in the exaggerated fibroblast proliferation seen in fibrosis [10]. Therefore, a rational therapeutic strategy for fibroproliferative disorders is to augment glutathione levels that would serve as protective screen to counterbalance toxic oxygen radicals.
For many years, N-acetyl-L-cysteine (NAC), a glutathione precursor, has been widely used as a mucolytic drug in pulmonary medicine [25]. The antioxidant potential of N-acetyl-L-cysteine has been established in vitro and in vivo. In vitro, the antioxidant capacity of N-acetyl-L-cysteine is directly related to the inactivation of electrophilic groups of free radicals [11, 12]. In vivo, N-acetyl-L-cysteine exerts its function as an antioxidant via its main metabolite, cysteine, the major precursor in the biosynthesis of glutathione [13]. In this respect, in paracetamol poisoning, oral N-acetyl-L-cysteine is able to replenish liver glutathione pools and to prevent drug-induced hepatotoxicity [14, 15]. In patients with lung tumours, oral treatment with N-acetyl-L-cysteine leads to an increase of glutathione levels in venous plasma and bronchoalveolar lavage fluid [16].
Oral N-acetyl-L-cysteine therapy in pulmonary fibrosis patients not only increased lung glutathione levels, but it did so with no short-term adverse effects. The therapy was safe, as judged by all routine clinical and bronchoscopic parameters evaluated [10].